Table 3.
Pharmacodynamic parameters of luseogliflozin after single (Day 1) and multiple (Day 7) doses of luseogliflozin compared with placebo
| Placebo (N = 8) | Luseogliflozin | ||||
|---|---|---|---|---|---|
| 0.5 mg (N = 7) | 1 mg (N = 8) | 2.5 mg (N = 8) | 5 mg (N = 8) | ||
| UGE0–24h (g) | |||||
| Baseline | 26.3 ± 19.7 | 33.5 ± 25.0 | 17.0 ± 15.3 | 44.1 ± 29.4 | 16.2 ± 14.0 |
| Day 1 | 26.9 ± 20.0 | 81.5 ± 33.2 | 75.1 ± 23.3 | 139 ± 31.1 | 116 ± 29.0 |
| Day 7 | 26.6 ± 17.8 | 81.7 ± 30.1 | 85.3 ± 18.8 | 131 ± 29.9 | 120 ± 33.1 |
| LS mean difference at Day 1a | – | 46.4 (32.9, 60.0)* | 58.9 (45.7, 72.1)* | 91.7 (78.1, 105)* | 101 (87.6, 114)* |
| LS mean difference at Day 7a | – | 49.2 (27.9, 70.5)* | 66.5 (45.8, 87.1)* | 89.4 (68.2, 111)* | 101 (80.7, 122)* |
| Plasma glucose | |||||
| C max0–4h (after breakfast) (mg/dL) | |||||
| Baseline | 290 ± 34.9 | 278 ± 42.7 | 266 ± 45.2 | 304 ± 54.3 | 262 ± 29.7 |
| Day 1 | 281 ± 42.1 | 278 ± 53.0 | 255 ± 44.1 | 254 ± 48.7 | 231 ± 16.6 |
| Day 7 | 269 ± 37.9 | 243 ± 42.1 | 240 ± 31.3 | 219 ± 26.3 | 222 ± 19.4 |
| LS mean difference at Day 1a | – | 7.49 (−16.9, 31.9) | −5.69 (−29.6, 18.2) | −38.4 (−62.0, −14.8)* | −26.2 (−50.3, −2.12)* |
| LS mean difference at Day 7a | – | −19.0 (−41.1, 3.04) | −15.5 (−37.1, 6.15) | −58.1 (−79.4, −36.7)* | −31.3 (−53.1, −9.47)* |
| C max4–8h (after lunch) (mg/dL) | |||||
| Baseline | 269 ± 30.5 | 302 ± 53.9 | 252 ± 35.6 | 293 ± 48.2 | 237 ± 30.6 |
| Day 1 | 270 ± 48.8 | 259 ± 52.3 | 223 ± 33.7 | 250 ± 54.5 | 207 ± 33.1 |
| Day 7 | 277 ± 40.8 | 256 ± 61.7 | 229 ± 33.7 | 230 ± 30.0 | 211 ± 35.1 |
| LS mean difference at Day 1a | – | −43.5 (−68.5, −18.5)* | −30.5 (−54.1, −7.02)* | −43.5 (−67.2, −19.7)* | −32.4 (−56.5, −8.28)* |
| LS mean difference at Day 7a | – | −46.2 (−76.1, −16.3)* | −34.7 (−62.8, −6.53)* | −65.6 (−94.0, −37.1)* | −41.0 (−69.8, −12.1)* |
| C max12–16h (after dinner) (mg/dL) | |||||
| Baseline | 273 ± 37.0 | 297 ± 42.4 | 277 ± 42.0 | 300 ± 47.9 | 252 ± 33.6 |
| Day 1 | 283 ± 39.1 | 286 ± 32.5 | 255 ± 37.3 | 279 ± 40.2 | 225 ± 33.2 |
| Day 7 | 269 ± 30.5 | 274 ± 34.6 | 242 ± 41.3 | 250 ± 23.3 | 223 ± 38.8 |
| LS mean difference at Day 1a | – | −16.0 (−35.0, 3.05) | −31.3 (−49.4, −13.3)* | −26.1 (−44.6, −7.60)* | −41.8 (−60.2, −23.5)* |
| LS mean difference at Day 7a | – | −9.79 (−35.5, 15.9) | −29.4 (−53.8, −5.06)* | −36.2 (−61.2, −11.3)* | −33.7 (−58.4, −9.02)* |
| AUC0–4h (after breakfast) (mg h/dL) | |||||
| Baseline | 972 ± 163 | 950 ± 178 | 886 ± 163 | 1020 ± 204 | 875 ± 109 |
| Day 1 | 935 ± 160 | 946 ± 175 | 812 ± 158 | 868 ± 166 | 752 ± 87.6 |
| Day 7 | 931 ± 162 | 810 ± 156 | 780 ± 116 | 738 ± 102 | 708 ± 87.5 |
| LS mean difference at Day 1a | – | 29.4 (−25.0, 83.8) | −48.9 (−102, 4.37) | −106 (−159, −53.6)* | −100 (−154, −46.5)* |
| LS mean difference at Day 7a | – | −108 (−186, −29.3)* | −96.7 (−173, −20.0)* | −221 (−297, −145)* | −162 (−239, −84.9)* |
| AUC4–8h (after lunch) (mg h/dL) | |||||
| Baseline | 965 ± 108 | 1060 ± 202 | 875 ± 158 | 1060 ± 199 | 829 ± 115 |
| Day 1 | 937 ± 168 | 915 ± 207 | 766 ± 131 | 879 ± 176 | 710 ± 120 |
| Day 7 | 986 ± 133 | 887 ± 209 | 787 ± 126 | 802 ± 127 | 710 ± 105 |
| LS mean difference at Day 1a | – | −111 (−191, −31.1)* | −89.1 (−166, −11.9)* | −147 (−224, −69.0)* | −104 (−183, −25.1)* |
| LS mean difference at Day 7a | – | −165 (−267, −64.2)* | −138 (−236, −40.8)* | −250 (−348, −152)* | −184 (−284, −84.3)* |
| AUC12–16h (after dinner) (mg h/dL) | |||||
| Baseline | 945 ± 117 | 1030 ± 165 | 944 ± 147 | 1050 ± 190 | 882 ± 127 |
| Day 1 | 943 ± 111 | 989 ± 114 | 851 ± 117 | 944 ± 123 | 766 ± 118 |
| Day 7 | 921 ± 91.7 | 924 ± 108 | 824 ± 125 | 828 ± 63.2 | 755 ± 137 |
| LS mean difference at Day 1a | – | −16.3 (−69.6, 37.0) | −91.4 (−142, −40.8)* | −71.1 (−123, −19.2)* | −133 (−184, −81.7)* |
| LS mean difference at Day 7a | – | −44.7 (−122, 32.2) | −96.2 (−169, −23.2)* | −149 (−224, −73.6)* | −131 (−205, −57.5)* |
| MPG0–16h (mg/dL) | |||||
| Baseline | 222 ± 31.6 | 233 ± 45.2 | 206 ± 34.7 | 238 ± 45.4 | 199 ± 26.8 |
| Day 1 | 220 ± 34.3 | 224 ± 38.8 | 188 ± 30.0 | 210 ± 35.7 | 173 ± 26.7 |
| Day 7 | 221 ± 32.9 | 204 ± 35.3 | 184 ± 24.0 | 181 ± 21.2 | 168 ± 27.8 |
| LS mean difference at Day 1a | – | −6.39 (−16.6, 3.79) | −18.4 (−28.3, −8.55)* | −23.8 (−33.7, −13.9)* | −27.4 (−37.4, −17.4)* |
| LS mean difference at Day 7a | – | −25.0 (−42.2, −7.90)* | −27.5 (−44.1, −10.8)* | −50.1 (−66.7, −33.4)* | −38.9 (−55.7, −22.1)* |
| FPG (24 h after dose) (mg/dL) | |||||
| Baseline | 167 ± 21 | 166 ± 29 | 151 ± 32 | 167 ± 38 | 150 ± 22 |
| Day 1 | 164 ± 21 | 156 ± 23 | 146 ± 25 | 141 ± 23 | 132 ± 12 |
| Day 7 | 163 ± 25 | 145 ± 18 | 139 ± 14 | 122 ± 14 | 126 ± 13 |
| LS mean difference at Day 1a | – | −7.15 (−16.0, 1.71) | −7.90 (−16.6, 0.795) | −23.0 (−31.6, −14.4)* | −20.8 (−29.5, −12.1)* |
| LS mean difference at Day 7a | – | −18.4 (−31.1, −5.75)* | −18.1 (−30.5, −5.62)* | −41.3 (−53.5, −29.0)* | −30.6 (−43.1, −18.1)* |
| Serum insulin | |||||
| AUC0–4h (after breakfast) (μIU h/mL) | |||||
| Baseline | 157 ± 74.2 | 92.2 ± 34.7 | 161 ± 54.7 | 119 ± 45.7 | 198 ± 132 |
| Day 1 | 168 ± 74.4 | 95.0 ± 33.9 | 161 ± 67.9 | 101 ± 56.1 | 190 ± 118 |
| Day 7 | 158 ± 78.6 | 81.4 ± 39.4 | 125 ± 43.4 | 75.1 ± 29.4 | 157 ± 82.5 |
| LS mean difference at Day 1a | – | −13.8 (−43.1, 15.6) | −12.1 (−39.4, 15.3) | −32.7 (−60.4, −4.93)* | −17.0 (−44.8, 10.8) |
| LS mean difference at Day 7a | – | −32.3 (−62.8, −1.82)* | −36.1 (−64.5, −7.72)* | −56.7 (−85.4, −27.9)* | −28.6 (−57.5, 0.198) |
| Urine volume (mL/day) | |||||
| Baseline | 2895.8 ± 1011.5 | 2881.3 ± 1004.2 | 2701.9 ± 592.4 | 3121.1 ± 1138.6 | 3372.1 ± 1413.1 |
| Day 1 | 2702.6 ± 1341.8 | 3148.1 ± 718.5 | 3284.5 ± 653.4 | 3511.4 ± 522.9 | 3939.8 ± 1386.0 |
| Day 7 | 2762.3 ± 1171.4 | 3053.3 ± 1067.7 | 2421.0 ± 795.6 | 3048.5 ± 868.2 | 3471.4 ± 1204.5 |
| LS mean difference at Day 1a | – | 456.1 (−212.4, 1124.7) | 723.8 (76.7, 1370.9)* | 643.8 (−3.8, 1291.3) | 888.4 (235, 1541.8)* |
| LS mean difference at Day 7a | – | 303.5 (−208.4, 815.3) | −174.9 (−670.3, 320.5) | 92.9 (−402.9, 588.6) | 300.4 (−199.9, 800.6) |
| Water intake (mL/day) | |||||
| Baseline | 2754.9 ± 1039.9 | 2630.9 ± 1044.0 | 2578.1 ± 602.5 | 3196.5 ± 1175.2 | 3311.3 ± 1429.3 |
| Day 1 | 2686.0 ± 1513.1 | 2694.4 ± 936.4 | 3023.8 ± 883.4 | 2964.0 ± 940.1 | 3256.8 ± 1581.7 |
| Day 7 | 2618.5 ± 1447.3 | 2686.4 ± 929.1 | 2400.4 ± 583.5 | 3049.1 ± 856.6 | 3141.0 ± 1387.3 |
| LS mean difference at Day 1a | – | 131.8 (−455.8, 719.3) | 513.6 (−54.5, 1081.7) | −161.3 (−733.9, 411.4) | 17.3 (−558.5, 593.1) |
| LS mean difference at Day 7a | – | 175.8 (−407.1, 758.7) | −64.4 (−628, 499.2) | 46.5 (−521.6, 614.6) | 38.5 (−532.7, 609.8) |
| Body weight (24 h after dose) (kg) | |||||
| Baseline | 75.96 ± 9.70 | 67.71 ± 14.40 | 72.13 ± 18.57 | 68.00 ± 7.90 | 71.80 ± 9.59 |
| Day 1 | 75.80 ± 9.63 | 67.49 ± 14.32 | 71.71 ± 18.26 | 67.43 ± 7.73 | 70.96 ± 9.34 |
| Day 7 | 75.28 ± 9.61 | 66.76 ± 14.29 | 71.01 ± 18.10 | 66.70 ± 7.84 | 70.24 ± 9.09 |
| LS mean difference at Day 1a | – | −0.19 (−0.58, 0.20) | −0.31 (−0.68, 0.07) | −0.53 (−0.91, −0.15)* | −0.74 (−1.11, −0.36)* |
| LS mean difference at Day 7a | – | −0.45 (−1.14, 0.24) | −0.51 (−1.17, 0.14) | −0.79 (−1.46, −0.12)* | −0.97 (−1.62, −0.31)* |
Values are presented as the mean ± standard deviation or LS mean (95% confidence interval)
AUC area under the plasma concentration–time curve, C max maximum plasma concentration, FPG fasting plasma glucose, LS least-squares, MPG 0–16h, mean plasma glucose from 0 to 16 h, UGE urinary glucose excretion
* P < 0.05
aData represent the LS mean difference (95% confidence interval) between each luseogliflozin group and placebo. The time-matched baseline on Day −1 was used as a covariate